ABSTRACT The focus of my research program is to improve our understanding of the molecular basis by which Amyloid ? (A?) 42 causes neurodegeneration and progression of Alzheimer?s Disease (AD) and to develop novel molecular therapeutics to slow or block neuropathology. We made the discovery that addition of mirror image ?D?-A?42 to a solution that contains the natural peptide (i.e., made of naturally occurring, L-amino acids) induces accelerated fibril formation and suppresses toxicity of the peptide. This is a fundamentally novel approach to inhibit A? toxicity and as such could pave the road to the development of new molecular therapeutics that operate through a unique mechanism of action. In Aim 1 we will conduct biophysical experiments to gain deeper insight into the molecular mechanisms that underlie this effect, which I refer to as Chiral Inactivation. We will study the mechanism of fibril formation from enantiopure peptides and their mixtures by conducting both kinetic studies and fibril composition analyses through various microscopy-based techniques. We will further investigate oligomer formation from both the enantiopure peptides and their mixtures, employing a combination of photochemical crosslinking techniques and low temperature trapping experiments followed by imaging of the aggregation intermediates. In Aim 2 we will deepen our understanding of biological function of the mixtures characterized under Aim 1. We will conduct mechanistic experiments in cell culture, probing the differentially pre-aggregated mixtures with regard to their toxicity in two cell lines. Collaborating with the Madison lab at Stanford, we will then study select mixtures with electrophysiology techniques, aimed to discern the mechanism of action at the functional level of highest relevance to AD, namely functional hippocampal neuronal networks. Studies performed through this R21 funding will provide the basis for a future R01 application, within the scope of which we will aim to develop frameworks that are inspired by the chiral inactivation approach, but are more drug-like, with the ultimate goal of creating a novel molecular therapeutic against AD.